Phase I Study of the Akt-Inhibitor Triciribine Phosphate Monohydrate in Patients with Advanced Hematologic Malignancy

Background: Akt is a key serine/threonine protein kinase commonly activated in hematologic malignancies that promotes cell survival through phosphorylation and activation of pathways such as IKKa-NFkB. In AML, constitutive Akt activation is associated with poor prognosis and may contribute to chemotherapy resistance. In vitro inhibition of Akt suppresses tumor cell growth, angiogenesis and metastasis, and induces apoptosis. Triciribine Phosphate Monohydrate (TCN-PM) is a small molecule inhibitor of Akt. Herein, we report results of a phase I dose-escalation clinical and pharmacodynamic (PD) study of TCN-PM in patients with advanced hematological malignancy.

Objectives: The primary objective of this dose escalation Phase I study is to determine safety, tolerability, and pharmacokinetic profile of TCN-PM in patients with advanced hematological cancers. Secondary objectives included assessment of TCN-PM on p-AKT status within leukemic blasts and clinical activity.

Eligibility: Patients with relapsed or refractory AML, ALL, CML-BC, MDS, and CLL were eligible.

Methods: TCN-PM was administered as a 1 hour IV infusion on days 1, 8, and 15 of each cycle. Cycles were repeated every 21 days. Patients were permitted to receive subsequent cycles, barring unacceptable toxicity or disease progression. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC). A dose limiting toxicity (DLT) was defined as any significant grade 3 or grade 4 toxicity during cycle 1. Peripheral blood (PB) for PK analysis was collected during cycle 1. In patients with circulating blasts, PB for PD studies (i.e. p-AKT status) was collected pre- and post-treatment with TCN-PM.

Results: 39 patients (27 M/12 F) were enrolled to date. Median age was 68 years (range, 30 – 79). Diagnoses included AML=31, MDS=4, CMML=2. Median number of prior therapies was 3 (range, 1 – 7). At the highest dose of 65 mg/m², one patient experienced DLT (grade 3 lipase and triglyceride elevation). Another patient treated at this dose developed hepatotoxicity (grade 3 bilirubin elevation) after 2 cycles. More common non dose-limiting non-hematologic toxicities included: dyspnea (n=4), fatigue (n=3); febrile neutropenia (n=3), hyperglycemia (n=3); others (n=6). Due to concerns for hepatic and metabolic toxicity, the MTD was declared at 55 mg/m². Pharmacokinetic studies indicated a dose dependent accumulation of TCN-P within leukemia blasts. In a xenograft nude mice model, TCN-PM significantly inhibits tumor growth in Akt-overexpressing cells, but not in tumors with low levels of Akt. In this regard, pharmacodynamic studies showed that 5/8 patients had a ratio of phosphorylated Akt/Akt indicating high Akt expression prior to therapy. Two of these patients treated at 35mg/m² demonstrated decreases in the ratio of phosphorylated Akt/Akt and phosphorylated Bad/Bad, consistent with an inhibition of this survival pathway and activity of triciribine in this patient population. Four patients treated at the 25 mg/m² or 35 mg/m² dose level experienced up to 50 percent reductions in peripheral blast cells. Additional hematological improvements included two patients achieving major improvements in platelet count lasting 7 and 36 days, respectively, and four patients achieving major improvements in neutrophil count lasting a median of 19 days. Another patient with CMML experienced a decrease in the WBC from > 100 × 10⁹/L to the normal range by cycle 3. There were no complete or partial responses.

Conclusions: Results from this dose escalation Phase I trial evaluating TCN-PM administered on a weekly schedule are encouraging and demonstrate at doses up to MTD is well-tolerated, with preliminary evidence of PD activity as measured by decreased blast p-AKT. Accrual at the MTD of 55 mg/m² is continuing. Future TCN-PM studies in hematological malignancies could enrich for patient populations where Akt is overexpressed.